KR101142052B1 - Method of preparing zanamivir - Google Patents

Abstract

The present invention relates to a method for economically and simply manufacturing a high yield of zanamivir, a flu therapeutic drug having neuraminidase inhibitory activity, to produce a high yield of zanamivir more economically and efficiently than a conventional method. can do.

Description

Method of manufacturing zanamivir {METHOD OF PREPARING ZANAMIVIR}

The present invention relates to a method for producing zanamivir, and more particularly, to a method for producing economical and convenient high yield of zanamivir, a flu therapeutic drug having neuraminidase inhibitory activity.

Janamivir (zanamivir (trade name: Rerenza)) is 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-gal having a structure of formula Lacto-non-2-enopyranosonic acid (5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid). Janamivir is a derivative based on the neuraminic acid skeleton and is marketed as a drug that inhibits the activity of neuraminidase obtained from cholera bacteria, Newcastle disease virus and influenza virus.

Until now, various methods for preparing zanamivir have been studied. For example, WO 91/16320 discloses a compound of Formula 2 using sulfur hydroxide and pyridine as shown in Scheme 1 below. A method of preparing zanamivir by reducing the compound of Formula 3, adding S-methylisourea to the compound of Formula 3 to synthesize a guanidino group, obtaining a compound, and then performing a continuous deprotection reaction in the same reactor. Doing.

[Reaction Scheme 1]

Wherein Ac is an acetyl group and Me is a methyl group.

However, the overall yield is very low as 13 ~ 14%, in particular, the reaction time in the guanidino group synthesis step takes 7 days at 5 ℃ and the yield is very low as 24% is difficult to apply industrially.

In addition, WO 94/07886 and M Von Itzstein et al. (M Von Itzstein et al., Carbohydrate research (1994), vol. 259, pp. 301-305) and MJ Bamford et al. (MJ Bamford et al., J. Chem. Soc. Perkin Trans 1 (1995), pp. 11731180 discloses a process for preparing zanamivir by synthesizing guanidino groups in the presence of a base from intermediate b. Specifically, in WO 94/07886, the base of triethylamine or imidazole and pyrazole-1H-carboxamidine monohydrochloride are simultaneously added at 30 ° C. to 50 ° C. as shown in Scheme 2 below. A method of synthesizing dino groups is disclosed, which requires a long reaction time of 18 hours. In addition, the method disclosed in the above papers was prepared by adding a base of triethylamine, sodium hydroxide and potassium carbonate at 20 ° C. and amino (imino) methanesulfonic acid at 20 ° C. to 40 ° C. as shown in Scheme 3 below. In order to synthesize the group, this method also requires a long reaction time of 16 hours or more, and the yield is 27 to 50%, which is difficult to apply industrially.

Scheme 2

Scheme 3

In order to synthesize zanamivir by the method of Scheme 2 or 3 above, intermediate b must be prepared. As a method for preparing intermediate b, WO 95/00503, WO 93/12105, M Von Itzstein et al. (M Von Itzstein et al., Carbohydrate) research (1994), vol. 259, pp. 301-305) and MJ Bamford et al. (MJ Bamford et al., J. Chem . Soc . Perkin Trans 1 (1995), pp. 11731180) and the like to obtain an intermediate b through a deprotection reaction after the deprotection reaction from the compound of formula (2) and a deprotection reaction after the reduction reaction from the compound of formula (2).

Scheme 4

Scheme 5

Specifically, in WO 93/12105 and M Von Itzstein et al., A deprotection process with triethylamine and sodium hydroxide after a reduction reaction using a Lindler catalyst, a palladium activated carbon, and hydrogen gas, a hydrogen donor, is shown in Scheme 4. In order to obtain compound b, this reaction requires a long reaction time of 20 hours, and has a disadvantage in that crystallization of the compound of formula (3) which is an intermediate is difficult. In addition, WO 95/00503, WO 93/12105, and Bamford et al. Disclose a method for synthesizing compound b as in Scheme 5, wherein triethylamine, 1,8-diazabicyclo [5, 4,0] Undeprotected reaction using undes-7-ene or sodium methoxide, intermediate b is obtained by using a Lindler catalyst and a hydrogen donor, formic acid or hydrogen gas. The disadvantage is that it takes time and crystallization of the intermediate compound c is difficult. In particular, the reduction reaction using hydrogen gas requires a bubbling process of hydrogen gas for 20 hours or more, which makes it difficult to safely apply to industrial production. In addition, the method of obtaining intermediate b by reducing after deprotection reaction requires an excessive amount of Lindler catalyst and formic acid, but it is difficult to complete the reaction. Above all, the most difficult part of the method for synthesizing zanamivir from intermediate b is that crystallization of compound b is not easy. The crystals of compound b are very fine, which results in poor filtration and good hygroscopicity, making the filtration more difficult. In particular, in the process of crystallizing the compound b, ie, in the process of crystallization through neutralization of the reaction solution, impurities of formic acid and a base derived from the Lindler catalyst may be included, thereby lowering the purity. In addition, the crystallization of Compound b by lyophilization is low in cost efficiency and difficult to require a long crystallization time.

Thus, the present inventors have developed a method of obtaining the compound of formula 3 from the compound of formula 2 by reduction under appropriate conditions, and subsequently obtaining the zanamivir of formula 1 by guanidino group synthesis reaction and deprotection reaction. The present invention has been completed by confirming that zanamivir can be produced by the above method in a shorter time than a conventional method with high purity and high yield.

WO199407886A1 WO199500503A1 WO199312105A1

M Von Itzstein et al., Carbohydrate research (1994), vol. 259, pp. 301-305 MJ Bamford et al., J. Chem. Soc. Perkin Trans 1 (1995), pp. 11731180

It is therefore an object of the present invention to provide a process for preparing zanamivir of formula 1 in high yield and high purity from a compound of formula 2 by successive reactions in the same reactor.

In order to achieve the above object, the present invention is 1) 5-acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5 of formula (2) -Trideoxy-D-glycero-D-galacto-non-2-enoic acid methylester monohydrate (5-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4- azido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid methyl ester monohydrate) is reacted with formic acid in a reaction solvent in the presence of a Lindler catalyst to obtain a compound of formula ; And 2) reacting the compound of formula 3 obtained in step 1) with pyrazole-1H-carboxamidine monohydrochloride in the presence of a base to obtain zanamivir of formula 1 It provides a method of manufacturing.

In the method of the present invention, the compound of formula 3 is obtained from the compound of formula 2 under appropriate conditions, and then the deprotection reaction and the synthesis of guanidino group are continuously performed in the same reactor, without further purification, compared with the conventional method. In a short time, zanamivir can be produced in high purity and high yield without the process of crystallization of intermediates.

Hereinafter, the present invention will be described in detail.

5-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycerol of the formula Reacting rho-D-galacto-non-2-enoic acid methylester monohydrate with formic acid in a reaction solvent in the presence of a Lindler catalyst to obtain a compound of formula 3 (Step 1); And 2) reacting the compound of formula 3 obtained in step 1) with pyrazole-1H-carboxamidine monohydrochloride in the presence of a base to obtain zanamivir of formula 1 (step 2) It provides a method for producing zanamivir of formula 1, characterized in that carried out continuously in the same reactor.

 [Formula 1]

[Formula 2]

(3)

Hereinafter, each step according to the present invention will be described in detail.

Step 1 of the process according to the invention is a step of preparing a compound of formula 3 which is an intermediate for the preparation of zanamivir by reducing the compound of formula 2. Step 1 is characterized in that to reduce the compound of formula (2) by using formic acid as a Lindler catalyst and a hydrogen donor to obtain a compound of formula (3).

In step 1 of the method according to the present invention, the Lindler catalyst is preferably used in an equivalent weight of 0.01 to 0.1, more preferably in the 0.05 ~ 0.07 equivalent weight. In addition, formic acid used as the hydrogen donor is preferably used in an amount of 1.4 to 2 molar equivalents, more preferably 1.5 to 1.7 molar equivalents. If the Lindler catalyst is used at 0.05 equivalent weight or less, the reaction will not be completed even if excessive formic acid is used. If the Lindler catalyst is used at 0.07 equivalent weight or more, it is difficult to remove excess impurities in the white solid. . In addition, when the formic acid is used in more than 1.7 molar equivalents, the reaction time may be shortened, but an excessive amount of impurities are generated. Therefore, when using 0.05 ~ 0.07 equivalent weight of Lindler catalyst and 1.5 ~ 1.7 molar equivalent of formic acid, the reaction can be optimized while minimizing this impurity.

The reaction solvent used in the method is preferably a mixed solvent of methanol and water, the mixing ratio of methanol and water is preferably a volume ratio of about 2: 1, the mixed solvent is used in an amount of 5 times based on the formula (2) It is desirable to be. When only a single solvent of methanol is used as the reaction solvent, the reaction does not proceed, and when only a single solvent of water is used, Compound 2 does not dissolve well, resulting in a very long reaction time. In addition, when the ratio of water to methanol is increased to 50% or more, there is a disadvantage that compound 2 is crystallized and the reaction time is long. When the volume of the mixed solvent is more than five times, it takes longer reaction time.

On the other hand, the reaction is preferably carried out at 50 to 55 ℃. When the reduction reaction is performed at a temperature of 60 ° C. or higher, the reaction time is shortened to less than 1 hour, but the color of the reaction solution becomes brown, and it is difficult to remove color when synthesizing zanamivir using it. There is a problem. If the reaction temperature is 50 ℃ or less, the reaction time is long, there is a problem that the purity is lowered.

Therefore, Chemical Formula 3 can be obtained with high purity within 2 hours under the conditions of 5 times the reaction solvent volume and the reaction temperature of 50 ~ 55 ℃.

The method for preparing the compound of formula 3 according to the present invention suppresses the generation of impurities of the Lindler catalyst and the formic acid by optimally and minimally using the Lindler catalyst and the formic acid, and when the above conditions are met, a reaction time known in the related art (20 hours) The compound of formula 3 can be obtained in much shorter time (1.5 hours) than

Step 2 of the process according to the invention is a step of reacting a compound of formula 3 with pyrazole-1H-carboxamidine monohydrochloride in the presence of a base to obtain zanamivir of formula 1. The reaction is characterized in that the guanidino group synthesis and deprotection reaction is carried out continuously without further purification.

Bases that may be used in this step include triethylamine, imidazole or 1,8-diazabicyclo [5,4,0] undes-7-ene, preferably 1,8-diazabicyclo [ 5,4,0] undes-7-ene, which base is preferably used in 5.5-6 molar equivalents. When the base is used at less than 5.5 molar equivalents, deprotection is not completed, and when used at more than 6 molar equivalents, there is a problem that the reaction does not proceed. In addition, the pyrazole-1H-carboxamidine monohydrochloride used to synthesize the guanidino group in the preparation method may be used in 3 to 5 molar equivalents, preferably 3.5 to 4.5 molar equivalents. have.

The reaction is preferably carried out at 70 to 75 ℃. In the reaction temperature conditions in the range of 50 ~ 60 ℃ takes a reaction time of more than 24 hours and there is a problem that the reaction is not completed even if 6 molar equivalents of pyrazole-1H-carboxamidine monohydrochloride. In addition, in the reaction temperature condition of 80 ~ 90 ℃ reaction time is 7 hours, the reaction time is short compared to the reaction at 70 ~ 75 ℃, but pyrazole-1H-carboxamidine monohydrochloride is decomposed at high temperature There is a problem that the reaction is not completed, there is a problem that requires more than 6 molar equivalents of pyrazole-1H-carboxamidine monohydrochloride. In addition, the reaction solution is dark brown at the reaction temperature of 80 ~ 90 ℃ range of the title compound to have a brown color instead of white, there is a problem that the color is not removed during purification.

According to the conditions as described above, the production method of the present invention proceeds the deprotection and the synthesis reaction of guanidino groups continuously in the same reactor, a time much shorter than the reaction time (16-18 hours) of the conventional method (9 hours The zanamivir can be obtained in), and the overall yield is 85-87%, and economical and efficient zanamivir can be obtained with a high purity of 97% or more.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 Preparation of Janamivir (Formula 1)

<Step 1> Methyl 5-acetamido-7,8,9-tri-O-acetyl-4-amido-2,3,4,5-tetradeoxy-D-glycero-D-galacto- Preparation of Non-2-enopyranosonate (Formula 3)

5-acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero represented by formula (2) To 30 g (0.063 mol) of D-galacto-non-2-enoic acid methyl ester monohydrate was dissolved by adding 150 mL of methanol and 75 mL of water. 1.5 g of Lindler catalyst and 3.57 mL (0.095 mol) of formic acid were added dropwise to the lysate, followed by heating to 50-55 ° C. and stirring for 1 hour 30 minutes. After the reaction was completed, the temperature of the reaction solution was slowly lowered to room temperature, filtered to remove the Lindler catalyst, and the obtained organic solution was distilled under reduced pressure to remove the solvent to obtain the title compound (27.2 g, yield: 100%). .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 6.00 (1H, d), 5.82 (1H, d), 5.47 (1H, m), 5.34 (1H, m), 4.64 (1H, dd), 4.51 (2H , m), 4.21 (1H, m), 3.88 (1H, m), 3.82 (3H, s), 2.14-2.00 (3H, m)

<Step 2> 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid (zanami Beer; Preparation of Formula 1)

The compound of formula 3 obtained in step 1 was dissolved in 548.7 mL of water and cooled to 5 ~ 10 ℃. 56.7 mL (0.38 mol) of 1,8-diazabicyclo [5,4,0] undes-7-ene was slowly added dropwise to the solution over 30 minutes, and then the temperature was increased to 70 to 75 ° C for 1 hour. Slowly rose over. When the temperature was 70-75 ° C., 37 g (0.25 mol) of pyrazole-1H-carboxamidine monohydrochloride was added, followed by stirring for 9 hours. When the reaction was completed, the temperature was slowly lowered to room temperature, and 2.7 L of ethyl alcohol was slowly added dropwise over 1 hour. After the solid was stirred at room temperature for 2 hours, the solid was filtered and washed with a mixture of ethyl alcohol and water to give the title compound (17.86 g, yield: 85%) as a white solid.

¹ H NMR (D ₂ O): δ 5.63 (1H, d), 4.42 (2H, m), 4.23 (1H, m), 3.93 (2H, m), 3.67 (2H, m), 2.04 (3H, s )

Claims (9)

1) 5-acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero of the formula Reacting -D-galacto-non-2-enoic acid methylester monohydrate with formic acid at 50 to 55 ° C. in a reaction solvent in the presence of a Lindler catalyst to obtain a compound of formula 3; And
2) reacting the compound of formula 3 obtained in step 1) with pyrazole-1H-carboxamidine monohydrochloride at 70-75 ° C. in the presence of a base to obtain zanamivir of formula 1 Continuously in the same reactor,
The reaction solvent is a mixed solvent of methanol and water,
The base is selected from triethylamine, imidazole, and 1,8-diazabicyclo [5,4,0] undes-7-ene.
[Formula 1]

(2)

(3)

The method of claim 1,
The Lindler catalyst of step 1 is characterized in that used in the equivalent weight of 0.01 to 0.1 based on the compound of Formula 2, zanamivir production method.
delete The method of claim 1,
The mixed solvent is methanol and water, characterized in that the mixture in a volume ratio of 2: 1, zanamivir production method.
The method of claim 1,
Formic acid of step 1, characterized in that used in 1.1 to 2 molar equivalents based on the compound of formula (2), the method for producing zanamivir.
delete The method of claim 1,
The base is 1,8-diazabicyclo [5,4,0] undes-7-ene, characterized in that it is used in 6 molar equivalents based on the compound of the formula (3), the method for producing zanamivir .
The method of claim 1,
The pyrazole-1H-carboxamidine monohydrochloride of step 2 is used in 3 to 5 molar equivalents based on the compound of Formula 3, the method for producing zanamivir. delete